Hyperlipemia is a state in which the amount of lipid increases in the blood. There are four (4) kinds of lipids in the blood—cholesterol, triglyceride (neutral fat), phospholipid and free fatty acid—and cholesterol and triglyceride especially cause clinical problems. Clinically, the following three states in which the amount of cholesterol has increased, the amount of triglyceride has increased, and the amount of both cholesterol and triglyceride has increased are generally called hyperlipemia.
In general, when the concentration of cholesterol is more than 220 mg/dl, triglyceride is more than 150 mg/dl, and HDL-cholesterol is less than 40 mg/dl in the blood serum while fasting, hyperlipemia is diagnosed.
In addition, with regard to the relationship between the cholesterol degree and the incidence rate of hyperlipemia, it is disclosed that when the LDL-cholesterol degree is lowered by 1%, the incidence rate is lowered by about 2%, and when 1 mg/dl of HDL-cholesterol is not taken, the incidence rate is lowered by about 3% (Castelli, JAMA 256:2835, 1986). From the above results, it is known that treating hyperlipemia can result in treating arteriosclerosis.
Generally, as the amount of ingestion of saturated fatty acid decreases and the cholesterol degree in the serum decreases, the incidence rate of ischemic heart disease (coronary artery disease) decreases. However, as the western style of meals and urban life increase the degree of cholesterol, ischemic heart disease also increases.
Therefore, studies and research to invent pharmaceutical agents to reduce the cholesterol degree are widely performed. As a result, pravastatin sodium was found to inhibit the generation of hydroxylmethylglutaryl Co-A (hereinafter, called “HMG Co-A”) in the biosynthesis of cholesterol, and was proved to have an effect to treat hyperlipemia.
Conventionally, pravastatin sodium was prepared by adding a precursor of the pravastatin such as compactin to a microorganism-culturing medium and culturing them. Microorganisms that can be used in this method comprise Streptomyces rhoseochromogenes NRRL-1233, Streptomyces rhoseochromogenes IFO-3363, Streptomyces rhoseochromogenes IFO-3411, or the like (U.S. Pat. No. 4,346,227).
Further, a method using Streptomyces exfoliatus YJ-118 to prepare the pravastatin sodium is disclosed in KR 210482 B.
However, when pravastatin sodium is prepared by culturing the above microorganisms, the growth of the microorganism is lowered because of the presence of the compactin, and therefore, compactin should be added with low concentration. As a result, the productivity of the pravastatin sodium is low and culturing time becomes long, which reduces efficiency.
At this point, the present inventors studied to prepare the pravastatin sodium with high productivity and efficiency. As seen above, the pravastatin sodium can inhibit generation of cholesterol and be used for treating hyperlipemia, but has the problem that its productivity is low when prepared by using conventional microorganisms, and thus, had a limitation in commercial use. As a result of the study, the present inventors have found that when pravastatin sodium is prepared by culturing a mutant Streptomyces carbophilus obtained by mutating Streptomyces carbophilus, its productivity becomes high, and have accomplished the present invention.